DJ-1 affects oxidative stress and pyroptosis in hippocampal neurons of Alzheimer's disease mouse model by regulating the Nrf2 pathway.

Abstract

Studies have confirmed that DJ-1 is associated with diseases associated with the nervous system, including Alzheimer's disease (AD). However, the role of DJ-1 in the pathogenesis of AD has not been clarified. To investigate the effect of DJ-1 on brain tissue damage and cognitive function in AD mice and its possible mechanism, 5XFAD transgenic mice were used as AD model mice and DJ-1 in the brain was overexpressed by transfection of a lentiviral containing a specific targeting DJ-1 gene into the bilateral hippocampus of mice. Following lentivirus infection, the Morris water maze test was performed to assess the cognitive function of the mice. When the behavioral evaluation was completed, the brain tissue of the mouse was examined. Pathological changes were observed by hematoxylin-eosin staining. The levels of relevant indicators were analyzed by reverse transcription-quantitative PCR, ELISA and western blotting. Bilateral hippocampal injection of a lentivirus containing DJ-1 significantly increased the expression of DJ-1 in the hippocampus of 5XFAD transgenic mice. Overexpression of DJ-1 in the brain could ameliorate brain tissue damage, β-amyloid protein (Aβ) deposition and cognitive function in 5XFAD mice. Compared with the sham group, the reactive oxygen species activity and malondialdehyde content in the brain tissue of DJ-1 overexpressing 5XFAD mice were significantly decreased, while the superoxide dismutase activity was significantly increased (P<0.05). In addition, DJ-1 overexpression decreased the expression of caspase-1 and the levels of interleukin (IL) 1β and IL-18 in the hippocampus while ameliorating the death of hippocampal neurons in 5XFAD mice and without affecting the expression of caspase-3. Overexpression of DJ-1 resulted in a significant decrease in nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in the cytoplasmic while significantly increasing the expression of Nrf2 in the nucleus. Simultaneously, DJ-1 overexpression in the brain inhibited the activation of nanoparticles activate the NLR pyrin domain containing 3 inflammatory bodies in brain tissue. Overexpression of DJ-1 in the brain could repair brain tissue damage, Aβ deposition and cognitive function in 5XFAD mice, and its mechanism may be associated with an inhibition of oxidative stress and neuronal pyroptosis by regulating the Nrf2 signaling pathway.